Sterile DJH Rearrangements Reveal that Distance Between Gene Segments on the Human Ig H Chain Locus Influences Their Ability To Rearrange

Hansen, Tina Østergaard; Lange, Anders Blaabjerg; Barington, Torben

doi:10.4049/jimmunol.1401443

Cited by 13 publications

(16 citation statements)

References 39 publications

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“…The size of the datasets enabled us to focus on non-productive sequence data, allowing us to exclude the possibility that observed biases were an outcome of selection acting upon transcribed genes. Significant differences in gene usage between productive and non-productive sequences were seen for some but not all D genes, confirming recent reports (26). These differences between IGHD genes may in part be explained by their varying utilization frequencies.…”

Section: Discussionsupporting

confidence: 90%

DJ Pairing during VDJ Recombination Shows Positional Biases That Vary among Individuals with Differing IGHD Locus Immunogenotypes

Kidd

Jackson

Boyd

et al. 2016

The Journal of Immunology

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Human immunoglobulin heavy chain diversity is influenced by biases in the pairing of IGHD and IGHJ genes, but these biases have not been described in detail. We have used high throughput sequencing of VDJ rearrangements to explore DJ pairing biases in twenty-nine individuals. It was possible to infer three contrasting IGHD-IGHJ haplotypes in nine of these individuals, and two of these haplotypes include deletion polymorphisms involving multiple contiguous IGHD genes. We were therefore able to explore how the underlying genetic makeup of the heavy chain locus influences the formation of particular DJ pairs. Analysis of non-productive rearrangements demonstrates that 3′ IGHD genes tend to pair preferentially with 5′ IGHJ genes, while 5′ IGHD genes pair preferentially with 3′ IGHJ genes, and the relationship between IGHD gene pairing frequencies and IGHD gene position is a near linear one for each IGHJ gene. Striking differences are seen, however, in individuals who carry deletion polymorphisms in the D locus. The absence of different blocks of IGHD genes lead to increases in the utilization frequencies of just a handful of genes, and these genes have no clear positional relationships to the deleted genes. This suggests that pairing frequencies may be influenced by additional complex positional relationships that arise perhaps from chromatin structure. In contrast to IGHD gene usage, IGHJ gene usage is unaffected by the IGHD gene deletion polymorphisms. Such an outcome would be expected if the recombinase complex associates first with an IGHJ gene, before associating with an IGHD gene partner.

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Section: Discussionsupporting

confidence: 90%

DJ Pairing during VDJ Recombination Shows Positional Biases That Vary among Individuals with Differing IGHD Locus Immunogenotypes

Kidd

Jackson

Boyd

et al. 2016

The Journal of Immunology

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“…Previous research has shown that the broad differences in gene usage are determined by the structure of these loci, such as gene copy number variation and proximity of V gene segments to the D and J loci5. However, the similarity of twins' CD4 + and CD8 + repertoires, as well as the similarity of the non-productive B-cell repertoires in twin-pairs, shows that these broadly defined patterns can be altered within an individual to create a unique repertoire.…”

Section: Discussionmentioning

confidence: 99%

“…Although the process of selecting gene segments for recombination is largely random, some are used more often than others. Studies have shown that overall biases in gene segment usage are the product of a variety of mechanisms, including a preferred recombination between certain V and (D)J segments2; receptor selection based on binding affinity for different major histocompatibility complexes (MHCs; for T-cell receptor (TCR) rearrangements)34; and bias based on the distance between V, D and J segments (for immunoglobulin (Ig) rearrangements)5. However, detailed studies using monozygotic (MZ) twins have shown that additional unidentified genetically encoded mechanisms must also contribute to the relative usage of individual gene segments678910.…”

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confidence: 99%

Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells

et al. 2016

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The adaptive immune system's capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, the influence of individual genetic and epigenetic differences on these repertoires is not typically measured. By leveraging the unique characteristics of B, CD4+ T and CD8+ T-lymphocyte subsets from monozygotic twins, we quantify the impact of heritable factors on both the V(D)J recombination process and on thymic selection. We show that the resulting biases in both V(D)J usage and N/P addition lengths, which are found in naïve and antigen experienced cells, contribute to significant variation in the CDR3 region. Moreover, we show that the relative usage of V and J gene segments is chromosomally biased, with ∼1.5 times as many rearrangements originating from a single chromosome. These data refine our understanding of the heritable mechanisms affecting the repertoire, and show that biases are evident on a chromosome-wide level.

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“…The method has been published in Barington et al : reads were qualified by the presence of primer and MID sequences and identical sequences (at least 1 forward and 1 reverse) were clustered. Clusters from the same PCR could be identified based on the primers and MIDs and were analyzed separately in the following: Clusters were evaluated by a numerical programming algorithm designed by the authors (details available from the corresponding author).…”

Section: Methodsmentioning

confidence: 99%

Evidence of perturbed germinal center dynamics, but preserved antibody diversity, in end‐stage renal disease

Assing

Nielsen

Jakobsen

et al. 2016

Immunity Inflam & Disease

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IntroductionEnd‐stage renal disease (ESRD) is associated with increased infectious susceptibility and with reduced vaccine responses consistent with compromised humoral immunity. Whether the compromised humoral immunity is due to reduced antibody diversity (reduced somatic hypermutation [SHM]) or altered germinal center (GC) dynamics is not known. The GC‐derived chemokine CXCL13 as well as peripheral T follicular helper cells (pTFH) reflect GC dynamics, but have, similar to SHM, never been characterized in relation to ESRD.MethodsSerum CXCL 13 was determined by ELISA. PTFH were flow‐cytometrically defined as CD4+ CD45RA− CCR7+ CXCR5+ lymphocytes. Apoptotic lymphocyte subsets were in addition annexin V+. SHM was determined, by next‐generation sequencing and bioinformatics, as nucleotide mutations within the IgG VH (comprising the important antigen‐binding domains of IgG, CDR1, and CDR2).ResultsElevated CXCL13 levels characterized ESRD (n = 19; [median] 90 pg/ml, P < 0.01) (controls, n = 18; 62 pg/ml). ESRD pTFH frequencies (n = 19; 11.6% [of CD4+ memory T cells], P < 0.02*, *Bonferroni corrected) (controls, n = 22; 14.9%) and concentrations (n = 19; 0.03 × 109/L, P < 0.02*) (controls, n = 22; 0.07 × 109/L) were reduced. ESRD pTFH were more apoptotic (n = 9; 25.7%, P = 0.04*) (controls, n = 10; 15.9%). SHM did not discriminate between ESRD (n = 10; 7.4%, P = 0.21) and controls (n = 10; 8.4%).ConclusionsElevated CXCL13 levels, reduced pTFH levels, and increased pTFH apoptosis suggest that perturbed GC dynamics, and not reduced antibody diversity, underlie the diminished vaccine responses and the compromised humoral immunity in ESRD. However, largely preserved SHM provides a rationale for pursuing vaccination in relation to ESRD.

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Sterile DJH Rearrangements Reveal that Distance Between Gene Segments on the Human Ig H Chain Locus Influences Their Ability To Rearrange

Cited by 13 publications

References 39 publications

DJ Pairing during VDJ Recombination Shows Positional Biases That Vary among Individuals with Differing IGHD Locus Immunogenotypes

DJ Pairing during VDJ Recombination Shows Positional Biases That Vary among Individuals with Differing IGHD Locus Immunogenotypes

Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells

Evidence of perturbed germinal center dynamics, but preserved antibody diversity, in end‐stage renal disease

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